Abstract

The p19ARF tumor suppressor (p14ARF in humans) is part of the ink4a locus and has been implicated in a variety of cancers. The traditional role for p19ARF has been in the stabilization of p53, a protein which is inactivated or mutated in 50% of tumors. However, it has been suggested that p19ARF has roles outside of this pathway. Evidence for this comes from mouse model studies that found mice lacking p19ARF and p53 develop a wider tumor spectrum and are more likely to have multiple tumors than mice lacking p53 alone. We have found that loss of p19ARF in mouse embryonic fibroblasts (MEFs) leads to a weakened mitotic checkpoint and aneuploidy. The mitotic checkpoint is the major cell cycle checkpoint regulating chromosome segregation and progression through mitosis. Defects in chromosome segregation produce progeny that are aneuploid, meaning they contain an abnormal chromosome number that deviates from a multiple of the haploid. The majority of cancers are aneuploid, which suggests that a dysfunctional mitotic checkpoint could play a role in tumorigenesis or cancer progression. In addition to a weakened mitotic checkpoint, loss of p19ARF leads to other mitotic defects including multipolar spindles, supernumerary centrosomes, and lagging chromosomes in anaphase. Future work will define the mechanism by which p19ARF functions in mitosis and establish an additional role in which p19ARF acts as a tumor suppressor.